This invention relates to a method of inhibiting nitric oxide formation in warm blooded mammals and, more particularly, to the administration of methyl-, dimethyl-, or amino-substituted guanidines as inhibitors of nitric oxide production in a host afflicted with acute or chronic inflammatory disease.
Nitric oxide synthase catalyzes the mixed functional oxidation of L-arginine to L-citrulline and nitric oxide (NO.spsp..) [Stuehr et al., Proc. Natl. Acad. Sci. USA 88, 7773 (1991)]. NO.spsp.. appears to function as either a signaling or an effector molecule depending on the isoform of the enzyme. The constitutive isoform of nitric oxide synthase produces small amounts of NO.spsp.. which activate guanylate cyclase resulting in the formation of cGMP which mediates endothelium-dependent relaxation [Moncada et al., Pharmacol. Reviews 43, 109 (1991)] and neural transmission [Garthwaite, Trends Neurol. Sci. 14, 60 (1991)]. NO.spsp.. is produced in much larger amounts by the cytokine and endotoxin inducible isoform of nitric oxide synthase, and in macrophages functions as an effector molecule which appears to mediate the cytotoxic actions of macrophages on target cells [Hibbs et al., Nitric Oxide from L-Arginine: a Bioregulatory System, S. Moncada and E. Higgs, Eds. Elsevier, N.Y. pp. 189-223 (1990)]. Since NO.spsp.. is a potent vasodilator and increases blood flow, and since vasoactive agents (such as histamine and bradykinin), which stimulate NO.spsp.. production increase both blood flow and vascular permeability, NO.spsp.. may be a candidate for mediating increases in blood flow and vascular permeability induced by diabetes and elevated glucose [Pugliese et al., Diabetes/Metabolism Reviews 7, 35 (1991)].
Recently, Interleukin-1 (IL-1) has been shown to induce the expression of the cytokine inducible isoform of nitric oxide synthase in pancreatic islets. The production of NO.spsp.. has been proposed to be the effector molecule which mediates IL-1's inhibitory effects on islet function [Southern et al., FEBS. Lett. 276, 42 (1990) and Corbett et al., Biochemical J. 287, 229 (1992)]. Generation of an IL-1-induced EPR detectable iron-nitrosyl complex, which is prevented by N.sup.G -monomethyl-L-arginine (NMMA), has been used to confirm the formation of nitric oxide by islets [Corbett et al., J. Biol. Chem. 266, pp. 21351-21354 (1991)]. Also, the protein synthesis inhibitor, cycloheximide has been shown to block IL-1-induced nitrite formation, cGMP accumulation, and EPR detectable iron-nitrosyl complex formation by islets, thus establishing that IL-1 induces the cytokine inducible isoform of nitric oxide synthase in pancreatic islets [Corbett et al., Biochemical J. 287, 229 ( 1992 )].
The pathogenesis of diabetic complications has been linked to imbalances in sorbitol, myo-inositol, and 1,2-diacyl-sn-glycerol metabolism, and to non-enzymatic glycation of cellular and extracellular constituents [Pugliese et al., Diabetes/Metabolism Reviews 7, 37 (1991)]. The glycation link is supported by evidence that aminoguanidine, a nucleophilic hydrazine compound, interferes with the formation of these glycation products and also attenuates the development of several diabetes-induced vascular [Pugliese et al., Diabetes/Metabolism Reviews 7, 35 (1991); Williamson et al., Diabete & Metab. 16, 3369 (1990); Soulis-Liparota et al., Diabetes 40, 1328 (1991)], neural [Kihara et al., Proc. Natl. Acad. Sci. USA 88, 6107 (1991)] and collagen changes [Brownlee et al., New Engl. J. Med. 318, 1315 (1988) and Brownlee et al., Science 232, 1629 (1986)]. Bucala et al., J. Clin. Invest. 87, 432 (1991) recently, reported that quenching of NO.spsp.. in vitro by glycated albumin is attenuated by aminoguanidine (present during exposure of albumin to glycating agents) and suggested that glycation products may impair endothelium-dependent relaxation by attenuating NO.spsp.. activity.